The Estrogen Related Receptor alpha (ERR) is an orphan nuclear receptor whose transcriptional activity is regulated by the expression level and/or activity of its obligate coregulators PGC-1 or PGC-1. Under normal physiological conditions, the ERR/PGC-1 complex is involved in regulating metabolic homeostasis in tissues in which energy demand is high. Motivated by the observation that elevated expression of ERR in both breast and ovarian tumors is associated with a poor clinical outcome, we developed a gene signature (metagene) that permitted a quantitative evaluation of ERR activity in tumors. Using this tool, it was determined that ERR activity is manifest in all breast tumor sub-types with particularly high activity being evident in ER-negative, HER2 positive, and triple negative breast cancers where it predicts a negative outcome. A causal role for ERR in breast cancer growth was confirmed in both cellular and xenograft models of breast cancer. Interestingly, it was also demonstrated that growth factor and/or PI3K-dependent activation of ERR/PGC-1 induces the expression of genes required for metabolic reprogramming in transformed cells and genes involved in angiogenesis, metastasis, and the establishment of the tumor microenvironment. Hypothesis: We propose that growth factor/oncogene-mediated upregulation of PGC-1 and/or PGC-1 expression results in the ERR-dependent activation of processes that contribute to tumor growth and metastasis. Specifically, it is hypothesized that this receptor contributes to cellular biomass accumulation by inducing the expression of key gene products required for the generation of biosynthetic intermediates and those which enable the adaptive responses underlying the differential use of glucose and lactate by cells in different tumor environments. ERR further reinforces these metabolic responses by regulating processes involved in (a) the establishment and maintenance of the tumor microenvironment, (b) angiogenesis, and (c) facilitating distant site metastasis. Specific Aims Aim 1: Define the rol of ERR in the metabolic reprogramming associated with breast tumor progression. Aim 2: Define the role of ERR in establishing and maintaining the tumor microenvironment in breast cancer. Aim 3: Define the impact of ERR on growth and metastasis in established models of breast cancer. Expected outcomes: Our data suggests that inhibition of ERR may have utility in the treatment of ER- negative, HER2 positive, and triple negative cancers where its activity is particularly evident. The studies outlined will advance this therapeutic approach by defining the importance of ERR as an integrator of cancer cell metabolism and of other non-metabolic pathways of pathological importance in cancer. We believe that the metabolic pathways upregulated by ERR in cancer are also manifest in healthy tissues with a high metabolic demand, and, thus, the insights from this work will be instructive as to the role of ERR in normal physiology.